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Special Issue Information

Dear Colleagues,

Bone is an active tissue that adapts to mechanical and physiological demands to maintain its structure and mineral homoeostasis. Bone remodeling is tightly regulated by hormones and other endocrine mediators that can be affected by nutrient deficiencies, food components, and a number of endogenous and environmental factors.

This Special Issue compiles original research and scientific perspectives providing information on:

Factors related to impaired bone health (worldwide perspective)

Impact of diet on bone metabolism disorders

Role of dietary macronutrients on bone homeostasis;

Role of dietary minerals on bone homeostasis;

Vitamin D deficiency and obesity

Recent findings on vitamin K and bone metabolism

Vitamins B and bone health

Role of bioactive food components on bone cells

Acid-base equilibrium and bone remodeling

Nutrigenetic and nutrigenomic aspects of bone health

Interactions between nutrition, physical activity, and lifestyle and their impact on bone health

Dr. M. Pilar VaqueroDr. Laura ToxquiGuest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Nutrients is an international peer-reviewed Open Access monthly journal published by MDPI.

Vegetarian diets are associated with factors that may not support bone health, such as low body mass and low intakes of protein; yet, these diets are alkaline, a factor that favors bone mineral density (BMD). This study compared the correlates of BMD in

Increased consumption of vegetables/herbs/fruit may reduce bone turnover and urinary calcium loss in post-menopausal women because of increased intake of polyphenols and potassium, but comparative human studies are lacking. The main aim was to compare bone turnover markers and urinary calcium excretion in

Limited evidence exists for an association between maternal diet during pregnancy and offspring bone health. In a prospective study, we examined the association between dietary patterns in mid-pregnancy and offspring forearm fractures. In total, 101,042 pregnancies were recruited to the Danish National Birth

Limited evidence exists for an association between maternal diet during pregnancy and offspring bone health. In a prospective study, we examined the association between dietary patterns in mid-pregnancy and offspring forearm fractures. In total, 101,042 pregnancies were recruited to the Danish National Birth Cohort (DNBC) during 1996–2002. Maternal diet was collected by a food frequency questionnaire. Associations were analyzed between seven dietary patterns extracted by principal component analysis and offspring first occurrence of any forearm fracture diagnosis, extracted from the Danish National Patient Register, between time of birth and end of follow-up (<16 year) (n = 53,922). In multivariable Cox regression models, offspring of mothers in the fourth vs. first quintile of the Western pattern had a significant increased risk (Hazard ratio, 95% confidence interval: 1.11, 1.01–1.23) of fractures, and there was a borderline significant positive trend (p = 0.06). The other dietary patterns showed no associations and neither did supplementary analyses of macro- and micronutrients or single food groups, except for the intake of artificially sweetened soft drinks, which was positively associated with offspring forearm fractures (p = 0.02). In the large prospective DNBC high mid-pregnancy consumption of Western diet and artificially sweetened soft drinks, respectively, indicated positive associations with offspring forearm fractures, which provides interesting hypotheses for future research.
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The association of high vitamin A intake and low bone mineral density (BMD) is still controversial. To determine the association of dietary vitamin A intake and serum 25-hydroxyvitamin D (25(OH)D) concentration with BMD, a total of 6481 subjects (2907 men and 3574 women)

The association of high vitamin A intake and low bone mineral density (BMD) is still controversial. To determine the association of dietary vitamin A intake and serum 25-hydroxyvitamin D (25(OH)D) concentration with BMD, a total of 6481 subjects (2907 men and 3574 women) aged ≥50 years from the Korean National Health and Nutrition Examination Survey (2008–2011) were divided into groups according to dietary vitamin A intake (tertiles) and serum 25(OH)D (<50, 50–75, >75 nmol/L), and evaluated for BMD after adjusting for relevant variables. Mean dietary vitamin A intakes were 737 and 600 μg RE (Retinol Equivalents) in men and women, respectively. Total hip and femoral neck BMD in men and lumbar spine BMD in women were both positively correlated with dietary vitamin A intake in subjects with serum 25(OH)D >75 nmol/L. Among men with serum 25(OH)D <50 nmol/L, both the top (mean 1353 μg RE) and bottom (mean 218 μg RE) tertiles of dietary vitamin A intake had lower BMD than the middle group (mean 577 μg RE). In this population, BMD was the highest among men and women with serum 25(OH)D = 50–75 nmol/L and that there were no differences in BMD by vitamin A intake in these vitamin D adequate groups. This cross-sectional study indicates that vitamin A intake does not affect bone mineral density as long as the serum 25(OH)D concentration is maintained in the moderate level of 50–75 nmol/L.
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The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats underwent either ovariectomy or sham operation (SHAM). The ovariectomized (OVX) rats were treated

The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats underwent either ovariectomy or sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX), estradiol valerate (EV), or RDE. After treatments, the bone mineral density (BMD) and the three-dimensional microarchitecture of the alveolar bone were analyzed to assess bone mass. Microarrays were used to evaluate microRNA expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of microRNAs was validated using real-time quantitative RT-PCR (qRT-PCR), and the target genes of validated microRNAs were predicted and further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using qRT-PCR. Our results show that RDE inhibits alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 8 microRNAs and downregulated expression levels of 8 microRNAs in the alveolar bone in the microarray analysis. qRT-PCR helped validate 13 of 16 differentially expressed microRNAs, and 114 putative target genes of the validated microRNAs were retrieved. The IPA showed that these putative target genes had the potential to code for proteins that were involved in the transforming growth factor (TGF)-β/bone morphogenetic proteins (BMPs)/Smad signaling pathway (Tgfbr2/Bmpr2, Smad3/4/5, and Bcl-2) and interleukin (IL)-6/oncostatin M (OSM)/Jak1/STAT3 signaling pathway (Jak1, STAT3, and Il6r). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may involve the simultaneous inhibition of bone formation and bone resorption, which is associated with modulation of the TGF-β/BMPs/Smad and the IL-6/OSM/Jak1/STAT3 signaling pathways via microRNA regulation.
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Osteoporosis is a highly prevalent skeletal disorder in the elderly that causes serious bone fractures. Peak bone mass achieved at adolescence has been shown to predict bone mass and osteoporosis related risk fracture later in life. Resveratrol, a natural polyphenol compound, may have

Osteoporosis is a highly prevalent skeletal disorder in the elderly that causes serious bone fractures. Peak bone mass achieved at adolescence has been shown to predict bone mass and osteoporosis related risk fracture later in life. Resveratrol, a natural polyphenol compound, may have the potential to promote bone formation and reduce bone resorption. However, it is unclear whether it can aid bone growth and bone mass accumulation during rapid growth and modulate bone metabolism during ageing. Using rat models, the current study investigated the potential effects of resveratrol supplementation during the rapid postnatal growth period and in late adulthood (early ageing) on bone microarchitecture and metabolism. In the growth trial, 4-week-old male hooded Wistar rats on a normal chow diet were given resveratrol (2.5 mg/kg/day) or vehicle control for 5 weeks. In the ageing trial, 6-month-old male hooded Wistar rats were treated with resveratrol (20 mg/kg/day) or vehicle for 3 months. Treatment effects in the tibia were examined by μ-computer tomography (μ-CT) analysis, bone histomorphometric measurements and reverse transcription-polymerase chain reaction (RT-PCR) gene expression analysis. Resveratrol treatment did not affect trabecular bone volume and bone remodeling indices in the youth animal model. Resveratrol supplementation in the early ageing rats tended to decrease trabecular bone volume, Sirt1 gene expression and increased expression of adipogenesis-related genes in bone, all of which were statistically insignificant. However, it decreased osteocalcin expression (p = 0.03). Furthermore, serum levels of bone resorption marker C-terminal telopeptides type I collagen (CTX-1) were significantly elevated in the resveratrol supplementation group (p = 0.02) with no changes observed in serum levels of bone formation marker alkaline phosphatase (ALP). These results in rat models suggest that resveratrol supplementation does not significantly affect bone volume during the rapid growth phase but may potentially have negative effects on male skeleton during early ageing.
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Aim: The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Methods: Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM). The

Aim: The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Methods: Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX) or RDE by oral gavage or with 17β-estradiol (E2) subcutaneously. After treatments, the bone mineral density (BMD), the three-dimensional bone architecture of the alveolar bone and the plasma biomarkers of bone turnover were analyzed to assess bone metabolism, and the histomorphometry of the alveolar bone was observed. Microarrays were used to evaluate gene expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of genes was further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using real-time quantitative RT-PCR (qRT-PCR). Results: Our results showed that RDE inhibited alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 207 genes and downregulated expression levels of 176 genes in the alveolar bone. The IPA showed that several genes had the potential to code for proteins that were involved in the Wnt/β-catenin signaling pathway (Wnt7a, Fzd2, Tcf3, Spp1, Frzb, Sfrp2 and Sfrp4) and the p38 MAPK signaling pathway (Il1rn and Mapk14). Conclusion: These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may be involved in the reduced abnormal bone remodeling, which is associated with the modulation of the Wnt/β-catenin and the p38 MAPK signaling pathways via gene regulation.
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Vitamin D insufficiency is a global health problem. The data on vitamin D status in Malaysian men is insufficient. This study aimed to investigate vitamin D status among Chinese and Malay men in Malaysia and its associating factors. A cross-sectional study was conducted

Vitamin D insufficiency is a global health problem. The data on vitamin D status in Malaysian men is insufficient. This study aimed to investigate vitamin D status among Chinese and Malay men in Malaysia and its associating factors. A cross-sectional study was conducted on 383 men aged 20 years and above, residing in Klang Valley, Malaysia. Their age, ethnicity, body anthropometry and calcaneal speed of sound (SOS) were recorded. Their fasting blood was collected for serum 25-hydroxyvitamin D (25(OH)D), intact parathyroid (PTH), total calcium and inorganic phosphate assays. Vitamin D deficiency was defined as a serum 25(OH)D level <30 nmol/L and insufficiency as a serum 25(OH)D level between 30 and 50 nmol/L. The overall prevalence of vitamin D deficiency was 0.5%, and insufficiency was 22.7%. Vitamin D deficiency and insufficiency were more prevalent in the Malays compared to the Chinese. Being Chinese, older in age, having lower body mass index (BMI) and a high physical activity status were associated significantly with a higher serum 25(OH)D level (p < 0.05). The serum PTH level was inversely associated with the serum 25(OH)D level (p < 0.05). As a conclusion, a significant proportion of Malaysian men have vitamin D insufficiency, although deficiency is uncommon. Steps should be taken to correct the vitamin D status of these men.
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This study aimed to evaluate the effects of annatto tocotrienol on indices of bone static histomorphometry in orchidectomized rats. Forty male rats were randomized into baseline (BL), sham (SH), orchidectomized (ORX), annatto tocotrienol-treated (AnTT) and testosterone enanthate-treated (TE) groups. The BL group was sacrificed upon receipt. All rats except the SH group underwent bilateral orchidectomy. Annatto tocotrienol at 60 mg/kg body weight was administered orally daily to the AnTT group for eight weeks. Testosterone enanthate at 7 mg/kg body weight was administered intramuscularly once weekly for eight weeks to the TE group. The rat femurs were collected for static histomorphometric analysis upon necropsy. The results indicated that the ORX group had significantly higher osteoclast surface and eroded surface, and significantly lower osteoblast surface, osteoid surface and osteoid volume compared to the SH group (p < 0.05). Annatto tocotrienol and testosterone enanthate intervention prevented all these changes (p < 0.05). The efficacy of annatto tocotrienol was on par with testosterone enanthate. In conclusion, annatto tocotrienol at 60 mg/kg can prevent the imbalance in bone remodeling caused by increased osteoclast and bone resorption, and decreased osteoblast and bone formation. This serves as a basis for the application of annatto tocotrienol in hypogonadal men as an antiosteoporotic agent.
Full article

Postmenopausal osteoporosis can be associated with oxidative stress and deterioration of antioxidant enzymes. It is mainly treated with estrogen replacement therapy (ERT). Although effective, ERT may cause adverse effects such as breast cancer and pulmonary embolism. Labisia pumila var. alata (LP), a herb

Postmenopausal osteoporosis can be associated with oxidative stress and deterioration of antioxidant enzymes. It is mainly treated with estrogen replacement therapy (ERT). Although effective, ERT may cause adverse effects such as breast cancer and pulmonary embolism. Labisia pumila var. alata (LP), a herb used traditionally for women’s health was found to protect against estrogen-deficient osteoporosis. An extensive study was conducted in a postmenopausal osteoporosis rat model using several LP doses and duration of treatments to determine if anti-oxidative mechanisms were involved in its bone protective effects. Ninety-six female Sprague-Dawley rats were randomly divided into six groups; baseline group (BL), sham-operated (Sham), ovariectomised control (OVXC), ovariectomised (OVX) and given 64.5 μg/kg of Premarin (ERT), ovariectomised and given 20 mg/kg of LP (LP20) and ovariectomised and given 100 mg/kg of LP (LP100). The groups were further subdivided to receive their respective treatments via daily oral gavages for three, six or nine weeks of treatment periods. Following euthanization, the femora were dissected out for bone oxidative measurements which include superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA) levels. Results: The SOD levels of the sham-operated and all the treatment groups were significantly higher than the OVX groups at all treatment periods. The GPx level of ERT and LP100 groups at the 9th week of treatment were significantly higher than the baseline and OVX groups. MDA level of the OVX group was significantly higher than all the other groups at weeks 6 and 9. The LP20 and LP100 groups at the 9th week of treatment had significantly lower MDA levels than the ERT group. There were no significant differences between LP20 and LP100 for all parameters. Thus, LP supplementations at both doses, which showed the best results at 9 weeks, may reduce oxidative stress which in turn may prevent bone loss via its anti-oxidative property.
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Because of ongoing global ageing, there is a rapid worldwide increase in incidence of osteoporotic fractures and the resultant morbidity and mortality associated with these fractures are expected to create a substantial economic burden. Dietary modification is one effective approach for prevention of

Because of ongoing global ageing, there is a rapid worldwide increase in incidence of osteoporotic fractures and the resultant morbidity and mortality associated with these fractures are expected to create a substantial economic burden. Dietary modification is one effective approach for prevention of osteoporosis in the general population. Recently, B vitamins have been investigated for their possible roles in bone health in human studies. In this review, we provide different lines of evidence and potential mechanisms of individual B vitamin in influencing bone structure, bone quality, bone mass and fracture risk from published peer-reviewed articles. These data support a possible protective role of B vitamins, particularly, B2, B6, folate and B12, in bone health. However, results from the clinical trials have not been promising in supporting the efficacy of B vitamin supplementation in fracture reduction. Future research should continue to investigate the underlying mechanistic pathways and consider interventional studies using dietary regimens with vitamin B enriched foods to avoid potential adverse effects of high-dose vitamin B supplementation. In addition, observational and interventional studies conducted in Asia are limited and thus require more attention due to a steep rise of osteoporosis and hip fracture incidence projected in this part of the world.
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Iron is essential in oxygen transport and participates in many enzymatic systems in the body, with important roles in collagen synthesis and vitamin D metabolism. The relationship between iron and bone health comes from clinical observations in iron overload patients who suffered bone

Iron is essential in oxygen transport and participates in many enzymatic systems in the body, with important roles in collagen synthesis and vitamin D metabolism. The relationship between iron and bone health comes from clinical observations in iron overload patients who suffered bone loss. The opposite scenario—whether iron deficiency, with or without anemia, affects bone metabolism—has not been fully addressed. This is of great interest, as this nutrient deficiency is a worldwide public health problem and at the same time osteoporosis and bone alterations are highly prevalent. This review presents current knowledge on nutritional iron deficiency and bone remodeling, the biomarkers to evaluate iron status and bone formation and resorption, and the link between iron and bone metabolism. Finally, it is hypothesized that chronic iron deficiency induces bone resorption and risk of osteoporosis, thus complete recovery from anemia and its prevention should be promoted in order to improve quality of life including bone health. Several mechanisms are suggested; hence, further investigation on the possible impact of chronic iron deficiency on the development of osteoporosis is needed.
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Nutrition is one of the most important modifiable factors involved in the development and maintenance of good bone health. Calcium and Vitamin D have confirmed and established roles in the maintenance of proper bone health. However, other nutritional factors could also be implicated.

Nutrition is one of the most important modifiable factors involved in the development and maintenance of good bone health. Calcium and Vitamin D have confirmed and established roles in the maintenance of proper bone health. However, other nutritional factors could also be implicated. This review will explore the emerging evidence of the supporting role of certain B Vitamins as modifiable factors associated with bone health. Individuals with high levels of homocysteine (hcy) exhibit reduced bone mineral density (BMD), alteration in microarchitecture and increased bone fragility. The pathophysiology caused by high serum homocysteine is not completely clear regarding fractures, but it may involve factors, such as bone mineral density, bone turnover, bone blood flow and collagen cross-linking. It is uncertain whether supplementation with B Vitamins, such as folate, Vitamin B1, and Vitamin B6, could decrease hip fracture incidence, but the results of further clinical trials should be awaited before a conclusion is drawn.
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Malnutrition is considered a leading cause of growth attenuation in children. When food is replenished, spontaneous catch-up (CU) growth usually occurs, bringing the child back to its original growth trajectory. However, in some cases, the CU growth is not complete, leading to a

Malnutrition is considered a leading cause of growth attenuation in children. When food is replenished, spontaneous catch-up (CU) growth usually occurs, bringing the child back to its original growth trajectory. However, in some cases, the CU growth is not complete, leading to a permanent growth deficit. This review summarizes our current knowledge regarding the mechanism regulating nutrition and growth, including systemic factors, such as insulin, growth hormone, insulin- like growth factor-1, vitamin D, fibroblast growth factor-21, etc., and local mechanisms, including autophagy, as well as regulators of transcription, protein synthesis, miRNAs and epigenetics. Studying the molecular mechanisms regulating CU growth may lead to the establishment of better nutritional and therapeutic regimens for more effective CU growth in children with malnutrition and growth abnormalities. It will be fascinating to follow this research in the coming years and to translate the knowledge gained to clinical benefit.
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